Intermittent hypoxia‐induced epiregulin expression by IL‐6 production in human coronary artery smooth muscle cells

Abstract

Patients with obstructive sleep apnea ( OSA ) experience repetitive episodes of desaturation and resaturation of blood oxygen (known as intermittent hypoxia or IH ), during sleep. We showed previously that IH induced excessive proliferation of rat vascular smooth muscle cells through upregulation of members of the epidermal growth factor family, especially epiregulin ( EREG ), and the erbB2 receptor. In this study, we exposed human coronary artery smooth muscle cells to IH and found that IH significantly increased the expression of EREG . IH increased the production of interleukin‐6 ( IL ‐6) in smooth muscle cells, and the addition of IL ‐6 induced EREG expression. Small interfering RNA for IL ‐6 or IL ‐6 receptor attenuated the IH ‐induced increase in EREG . IL ‐6 may play a pivotal role in EREG upregulation by IH and consequently OSA ‐related atherosclerosis.

Proliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia

“…Our in vitro model confirmed that IH increased IL-6 in human coronary artery smooth muscle cells (hCASMCs) [35]. Similarly, increases of IL-6 and IL-8 with IH have been observed in both human endothelial cells and cardiac myocytes [44,67,80].…”

“…On the other hand, our study of RASMCs found that sustained hypoxia (1% O 2 ) induced a large increase of GLUT1 mRNA and IH which led to a very slight increase of GLUT1 mRNA [63]. Furthermore, IH has been shown to significantly increase IL-6 expression, which is mainly mediated by NF-κB rather than HIF-1 [35]. In conjunction with the studies showing the involvement of NF-κB in IH, these results suggest that, in VSMCs, HIF-1 has more difficulty functioning in response to IH, as compared with NF-κB .…”

“…The IL-6 amplifier may also be present, due to the simultaneous activations of the nuclear factor NF-κB and the signal transducer and activator of transcription 3 (STAT3), which increases the expression of chemokines in non-immune cells and induces inflammation via a NF-κB loop, resulting in the accumulation of various immune cells and the dysregulation of homeostasis. The IL-6 amplifier is also thought to be associated with a number of diseases and disorders [81,82,83] as well as cardiovascular diseases, including atherosclerosis, in patients with OSA, since IH activates both NF-κB (via hypoxic conditions) and STAT3 (via increased IL-6) [34,35,43,61,83].…”

“…Recently, our laboratory demonstrated that IH directly increased the number of VSMCs by increasing the epidermal growth factor (EGF) family ligands and the EGF receptor erbB2, which were partially mediated by the IH-induced increase of interleukin (IL)-6 [34,35]. In the present review, we summarize the effects of IH on VSMCs, focusing on the intracellular mechanisms related to atherosclerosis, and develop a discussion of other chronic inflammatory diseases (CID).…”

Intermittent Hypoxia Up-Regulates Gene Expressions of Peptide YY (PYY), Glucagon-like Peptide-1 (GLP-1), and Neurotensin (NTS) in Enteroendocrine Cells

“…The serial dilutions were run to verify the specificity and to test the sensitivity of the SYBR Green-based real-time RT-PCR. The respective mRNA levels were normalized by those of the β-actin mRNA for human, by those of Rig/RpS15 mRNA for mouse mRNAs, and the miR levels were normalized by U6 RNA level as an internal standard [4,20,22,25,26,27,28,29].…”